Maintenance Therapy of Childhood ALL : longitudinal Profiles of Blood Counts and Their Association

Acute lymphoblastic leukemia is the most common cancer among children aged 1 to 15 years. The treatment consists of three parts, where the maintenance therapy (the last part) is the longest part of the treatment. During maintenance therapy, doses of oral chemotherapy are adjusted in response to frequent measurements of white blood counts (WBC), absolute neutrophile count (ANC) and absolute lymphocyte count (ALC). Currently there exists no general guidelines for how the doses of the drugs are adjusted optimally. In the Nordic countries doses are adjusted according to white blood count (WBC). However, this is not associated with the risk of relapse, but instead ANC has turned out to be associated with the risk of relapse. Due to this finding it is currently discussed whether ANC should be used for dose adjustment instead of WBC. In this thesis, we use a large data set to examine the longitudinal profiles for WBC, ANC and ALC during maintenance therapy. The purpose is to see whether these blood counts share some of the same features as well as to determine their association. In the context of linear mixed models, we consider univariate models for each outcome to examine each of the profiles. To investigate the correlation and to compare profiles, the univariate mixed models are combined in a multivariate model. With several outcomes, the parameters in the multivariate model cannot be estimated because of a large number of random effects, but instead a pairwise modelling strategy based on pseudo-likelihoods is implemented. We find some differences in subgroups with respect to their longitudinal profiles. Furthermore, the profiles for the blood counts share some, but not all, features. In particular we find that the processes do not run in parallel. ANC is constant in the maintenance therapy, whereas WBC and ALC decreases. Moreover, we find that WBC and ANC are highly correlated with a correlation of approximately 0.8, the correlation between WBC